Injectable meclizine formulations and methods

ABSTRACT

Methods of treating or preventing a vertigo, nausea, or vomiting condition comprising injecting a subject with a pharmaceutically acceptable formulation consisting essentially of an effective amount of meclizine or a pharmaceutically acceptable salt thereof, a chemically modified cyclodextrin, and an aqueous carrier medium having a pH between about 2 and about 7 are disclosed. An injectable pharmaceutical formulation for treating or preventing a vertigo, nausea, or vomiting condition consisting essentially of an effective amount of meclizine, a chemically modified cyclodextrin, and an aqueous carrier medium having a pH between about 2 and about 7 is also disclosed.

BACKGROUND Field

This invention relates to methods of treating vertigo conditions byadministration of an injectable pharmaceutical formulation comprisingmeclizine and a chemically modified cyclodextrin. This invention furtherrelates to methods of treating nausea or vomiting conditions byadministration of an injectable pharmaceutical formulation comprisingmeclizine and a chemically modified cyclodextrin.

Vertigo is a disabling disorder. The most common cause of vertigo isbenign paroxysmal positional vertigo (BPPV). Vertigo may be a symptom ofan underlying cause, such as in BPPV, or it may be suggestive of a moreserious problem such as drug toxicities (e.g., gentamicin), strokes ortumors. Vertigo may be comorbid with skull fractures or brain trauma,sudden changes of blood pressure, or as a symptom of motion sickness.Vertigo may cause or include extreme dizziness, nausea, or vomitingepisodes.

Nausea is a sensation of unease and discomfort in the stomach, usuallyaccompanied by an urge to vomit. Nausea is medically not an illness; itis a symptom of several conditions, many of which may not be related tothe stomach. Nausea may be indicative of an underlying conditionelsewhere in the body. Motion sickness, which is due to confusionbetween perceived and actual movement, is an example. Nausea may resultas an adverse effect of a drug. Nausea may be a problem during somechemotherapy regimens and following general anesthesia.

There are several types of anti-emetics, however, many pharmacologicaltreatments, which are effective for nausea and vomiting in some medicalconditions, may not be effective for other medical conditions. Forexample, metoclopramide and prochlorperazine, although widely used asanti-emetics, are ineffective for motion-sickness prevention andtreatment.

Once vomiting has commenced, oral anti-emetic treatments becomesubstantially ineffective. This may be because the orally administereddrug may not be retained for a sufficient period of time to allowabsorption from the stomach. Oral anti-emetic drugs may require up to45-90 minutes for achieving their clinical effect and are thus noteffective in treating expected vomiting episodes. In order for oraltreatment regimes to be effective, the regimes would necessarily need tobe ingested 1-2 hours prior to the expected vomiting episode. The netresult is longer ER visits and often hospital admissions for patientswith nausea-related conditions. Moreover, this limitation of oralanti-emetics makes them unsuitable for administration topost-anesthetized or unconscious subjects.

Intravenous anti-emetics are few in number, for example, cyclizine, maycurrently offer an alternative to oral anti-emetic therapies for thetreatment and prevention of nausea and vomiting, however, it presentswith a very short duration of action (1-2 hours). Such short duration ofaction limits the clinical application of cyclizine.

Meclizine is commercially available as an oral and as a chewable tablet.It is used in the treatment and prevention of nausea and vertigoassociated with Meniere's syndrome and in the treatment and preventionof motion sickness. It has also been used for the symptomatic treatmentrelief of hypersensitivity reactions and in pruritic skin disorders. SeeMartindale 30, 941. It is usually given in divided daily doses of 25-50mg, with divided daily doses of up to 100 mg being used to treat severevertigo and labyrinth disorders. Both meclizine base and meclizine HClhave been administered by the rectal route in similar doses to thoseadministered by mouth. There are, however, no marketed meclizine rectalpreparations. See Martindale 30, 941. There are also currently nomarketed hypodermically administrable meclizine HCl formulationsavailable. This may be attributed primarily to the poor aqueoussolubility of meclizine HCl. Meclizine is virtually water insoluble,with meclizine HCl presenting with a water solubility of 0.1 g/100 ml.Merck Index, 12th Ed, 984. In particular, meclizine exhibits very lowsolubility at pH values greater than 2.0. Such pH values are desirablefor reasons of injection comfort. Meclizine's anti-emetic duration ofaction may last up to 24 hours.

Thus, there is a need to provide stable, non-colloidal, injectableanti-emetic therapeutic formulations with longer duration of action,such as 12-24 hours. There is a need to provide otherwise insolubleand/or unstable anti-emetics, such as meclizine, as injectabletherapeutic formulations for the treatment and prevention of nausea andvertigo. There is also a need to provide a viable hypodermic formulationfor the treatment of nausea and vomiting as a clinically effectivealternative to oral dosage forms.

SUMMARY

In an embodiment, a method of treating a vertigo condition in a subjectin need thereof is provided. The method comprises injecting the subjectwith a pharmaceutically acceptable formulation consisting essentially ofa therapeutically effective amount of meclizine, a chemically modifiedcyclodextrin, where the molar ratio of the meclizine to the chemicallymodified cyclodextrin is 1:>1, and an aqueous carrier medium having a pHbetween about 2 to about 7. Optionally, a pharmaceutically acceptablepreservative, a pharmaceutically acceptable antioxidant, apharmaceutically acceptable osmolality adjusting agent, or mixturesthereof, may be added.

In another embodiment, an injectable pharmaceutical formulation fortreating a vertigo condition of a subject is provided. The injectablepharmaceutical formulation consists essentially of a therapeuticallyeffective amount of meclizine, a molar excess of2-hydroxypropyl-β-cyclodextrin, and an aqueous carrier medium. Theaqueous carrier medium has a pH between about 2 to about 7. Optionally,a pharmaceutically acceptable preservative, a pharmaceuticallyacceptable antioxidant, a pharmaceutically acceptable osmolalityadjusting agent, or combination thereof, may be added.

In another embodiment, an injectable pharmaceutical formulation fortreating and/or preventing a vertigo, nausea, or vomiting condition in asubject in need thereof is prepared by the steps of providing achemically modified cyclodextrin solution in a pharmaceuticallyacceptable aqueous carrier medium, combining a therapeutically effectiveamount of meclizine with the chemically modified cyclodextrin solution,and adjusting the pharmaceutically acceptable aqueous carrier medium pHto between about 2 to about 7. The molar ratio of the meclizine to thechemically modified cyclodextrin solution is 1:>1. Optionally, apharmaceutically acceptable preservative, a pharmaceutically acceptableantioxidant, a pharmaceutically acceptable osmolality adjusting agent,or combination thereof, may be added.

In another embodiment, a method of treating or preventing a nausea orvomiting condition in a subject in need thereof is provided. The methodcomprises injecting a subject with a pharmaceutically acceptableformulation consisting essentially of a therapeutically effective amountof meclizine, a chemically modified cyclodextrin, where the molar ratioof the meclizine to the chemically modified cyclodextrin is 1:>1, and anaqueous carrier medium having a pH between about 2 to about 7.Optionally, a pharmaceutically acceptable preservative, apharmaceutically acceptable antioxidant, a pharmaceutically acceptableosmolality adjusting agent, or mixtures thereof may be added.

In another embodiment, an injectable pharmaceutical formulation fortreating or preventing a nausea or vomiting condition is provided. Theinjectable pharmaceutical formulation consists essentially of atherapeutically effective amount of meclizine, a molar excess of2-hydroxypropyl-β-cyclodextrin, and an aqueous carrier medium. Theaqueous carrier medium has a pH between about 2 to about 7. Optionally,a pharmaceutically acceptable preservative, a pharmaceuticallyacceptable antioxidant, a pharmaceutically acceptable osmolalityadjusting agent, or combination thereof, may be added.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts graphically the effect of pH (0.1 M citric acid buffer)on the aqueous solubility of meclizine.

FIG. 1A depicts graphically the relationship of meclizine concentrationwith increasing cyclodextrin concentration in ddH₂O.

FIG. 2 depicts graphically the effect of increasing concentrations of2-hydroxypropyl-o-cyclodextrin (HPBCD) and sulfobutylether-P-cyclodextrin (SBECD) on the aqueous solubility of meclizine in0.5 M citric acid buffer at pH 3.0.

FIG. 2A depicts graphically the pH-dependent solubility of meclizinecyclodextrin complexes in 0.5 M citric acid buffer.

FIG. 3 depicts graphically the effect of increasing concentrations of2-hydroxypropyl-β-cyclodextrin (HPBCD) and sulfobutylether-β-cyclodextrin (SBECD) on the aqueous solubility of meclizine in0.5 M citric acid buffer at pH 4.0.

DETAILED DESCRIPTION

An injectable pharmaceutical formulation consisting essentially ofmeclizine and a chemically modified cyclodextrin is described.Formulations according to the invention are stable, non-colloidalaqueous solutions containing up to 100 mg/ml meclizine for hypodermicadministration.

The meclizine/cyclodextrin pharmaceutical formulations are suitable foradministration to a subject in need thereof of treatment of a vertigo,nausea, or vomiting condition. The meclizine/cyclodextrin formulationsprovides for methods of treating or preventing a vertigo, nausea, orvomiting condition or related complication. The meclizine/cyclodextrinformulations also provides for administration of a hypodermicallyeffective amount of a meclizine/cyclodextrin formulation to anunconscious or post-anesthesized subject treating or preventing avertigo, nausea, or vomiting condition. Preparation ofmeclizine/cyclodextrin formulations suitable for direct orreconstitutable hypodermic administration is also provided. Compositionsconsisting of stable non-colloidal aqueous solutions contain up to 100mg/ml of meclizine suitable for hypodermic administration are described.

Prior to describing the methods herein disclosed in further detail,however, the following terms will first be defined.

DEFINITIONS

The terms “meclizine” or “meclozine” are used interchangeably and referto the compound having the chemical name1-(4-chlorobenzhydryl)-4-(3-methylbenzyl)-piperazine. The term“meclizine” includes, meclizine base, its pharmaceutically acceptablesalts, for example, meclizine•2HCl1-(4-chlorobenzhydryl)-4-(3-methylbenzyl)-piperazine dihydrochloride, orits hydrates. Other pharmaceutically acceptable salts of meclizine basemay be used. Meclizine•2HCl monohydrate is generally preferred.

As used herein, the phrase “nausea or vomiting condition” refers tosymptoms normally associated with nausea or emesis. The phrase “nauseaor vomiting condition” includes nausea- or vomiting-related disorders.

As used herein, the phrase “vertigo condition” refers to symptomsnormally associated with vertigo. The phrase “vertigo condition”includes vertigo-related disorders.

As used herein, the term “prevent” and its grammatical equivalents referto any reduction of a subject's predisposition or risk for developing anausea or vomiting condition. The term “prevent” includes eitherpreventing a clinically evident nausea or vomiting condition fromoccurring altogether or preventing a pre-clinically evident nausea orvomiting condition in an individual at risk for such a condition fromoccurring. For example, the term “prevent” includes any reduction of asubject's predisposition or risk for developing a nausea or vomitingcondition as a result of chemotherapy regimens and/or pre-, peri-, orpost-anesthesia.

As used herein, the term “treatment” and its grammatical equivalentsrefer to the alleviation or elimination of symptoms and include, forexample, the elimination of such symptom causation either on a temporaryor permanent basis, or to alter or slow the appearance of such symptomsor symptom worsening. For example, the term “treatment” includesalleviation or elimination of causation of symptoms associated with, butnot limited to, vertigo, nausea, vomiting, or any vertigo, nausea, orvomiting related-complications described herein.

“Therapeutically effective” as used herein, refers qualitatively to theamount of meclizine that will achieve the goal of preventing orimproving in the severity of, the nausea, vomiting, or vertigo conditionbeing treated. A vertigo, nausea, or vomiting condition symptom or itsrelated complication is considered ameliorated or improved if anybenefit is achieved, irrespective of the absolute magnitude of theamelioration or improvement. For example, any reduction in nausea of asubject suffering from a nausea condition, such as post-anestheticnausea, would be considered an ameliorated symptom. Likewise, anyinhibition or suppression of vomiting would also be consideredamelioration of a vomiting condition. Furthermore, any reduction insymptom severity of a vertigo condition or its related complication isconsidered an ameliorated symptom of a vertigo condition.

As used herein, “therapeutically effective amount” refers to an amountof meclizine that is nontoxic but sufficient in preventing orameliorating the severity of the nausea-, vomiting-, or vertigo-relatedcondition being treated. For example, a therapeutically effective amountof meclizine is an amount sufficient to measurably decrease the symptomor etiology of a nausea condition. The therapeutically effective amountvaries according to the patient's sex, age and weight, the route ofadministration, the nature of the condition and any treatments that maybe associated therewith, or any concurrent related or unrelatedtreatments or conditions of the patient. Therapeutically effectiveamounts can be determined without undue experimentation by any person ofordinary skill in the art or by following the exemplary guidelines setforth in this application.

As used herein, the term “subject” for purposes of treatment includesany subject, and preferably is a subject who is in need of treatment ofa vertigo, nausea, or vomiting condition. For purposes of prevention,the subject is any subject, and preferably is a subject that is at riskfor, or is predisposed to, developing a vertigo, nausea, or vomitingcondition. The subject is typically an animal, more typically is amammal. Preferably, the mammal is a human.

The subject may be a human subject who is at risk for developing or isexperiencing a vertigo, nausea, or vomiting condition. The subject maybe at risk or experiencing such a condition due to geneticpredisposition, diet, age, post-exposure to an anesthetic, head trauma,exposure to a potentially traumatic environment, exposure to nausea- orvomiting-causing agents or environment, and the like. The subject mayalso be at risk or experiencing such a condition due to physiologicalfactors such as anatomical and/or biochemical abnormalities.

As used herein, “subject in need thereof” refers to any subject who issuffering from or is predisposed to a vertigo, nausea, or vomitingcondition.

The terms “hypodermic,” and “injection,” and their grammaticalequivalents are used interchangeably and refer to any delivery methodsuitably adapted for administering a solution to a subject. For example,“hypodermic” includes delivery methods comprising the use of a syringe,microneedle, or needleless device.

The term “injectable pharmaceutical formulation” refers generally to apharmaceutical formulation comprising a therapeutically effective amountof a meclizine such that the pharmaceutical formulation is suitable forinjection into a subject. For example, an “injectable pharmaceuticalformulation” of a meclizine inclusion complex with a cyclodextrincomprises a therapeutically effective amount of meclizine and issuitable for injection into a subject. Preferably, the “injectablepharmaceutical formulation” is a clear, non-colloidal solution of ameclizine, or its inclusion complex, with a cyclodextrin.

The term “chemically modified cyclodextrin” refers to one or morechemically modified cyclodextrins where there is independently more thanone degree of substitution that may vary from about 0.5 to about 10.0.The degree of substitution (the mean number of functional groups perglucose unit) of the chemically modified cyclodextrin may vary as needto provide the necessary solubility and stability of the meclizine. Forexample, the degree of substitution may be between from about 0.5 toabout 10.0. For a chemically modified cyclodextrin such as2-hydroxypropyl-β-cyclodextrin, the degree of substitution (ofsubstituted hydroxy functional groups per glucose unit) may be between3.9 and 5.1, for example. Degree of substitution may be determined bymass spectrometry (MS) or nuclear magnetic resonance (NMR) spectroscopyusing known techniques.

As used herein, “comprising,” “including,” “containing,” “characterizedby,” and grammatical equivalents thereof are inclusive or open-endedterms that do not exclude additional, unrecited elements or methodsteps. “Comprising” is to be interpreted as including the morerestrictive terms “consisting of” and “consisting essentially of.”

As used herein, “consisting of” and grammatical equivalents thereofexclude any element, step, or ingredient not specified in the claim.

As used herein, “consisting essentially of” and grammatical equivalentsthereof limit the scope of a claim to the specified materials or stepsand those that do not materially affect the basic and novelcharacteristic or characteristics of the claimed subject matter. Forexample, specified materials or steps that do not materially affect thebasic and novel characteristics of the claimed subject matter wouldinclude compounds or compositions of matter present at a level which donot directly attribute to or are capable of treating or preventing avertigo, nausea, or vomiting condition in a subject.

Cyclodextrins

Cyclodextrins suitable for use in the compositions, formulations, andmethods herein disclosed are generally cyclic oligosaccharides with acone-like shape. The interior of the cone acts as a hydrophobic cavity,while the exterior of the cone is hydrophilic. The former propertyenables cyclodextrins to form inclusion complexes with a wide variety oflipophilic molecules or portions thereof, which “fit” into the cavitywhile the latter property facilitates aqueous solubility. Cyclodextrinderivatives have been extensively studied for use as parenteral drugcarriers owing to their high water solubility and low toxicity.Cyclodextrins in Pharmacy. Fromming, K H & Szejtli, J. 1994. KluwerAcademic Publishers, pp 1-44. Clinical studies on healthy volunteersshowed, for example, that an intravenous infusion of Encapsin-HPB©(parenteral grade 2-hydroxypropyl-β-cyclodextrin, Janssen Pharmaceutica)at a dose of 3 g, given as a single dose, was safe and well tolerated.Junge et al., Janssen Clinical Research Report, July 1988.

Chemically Modified Cyclodextrins

The cyclodextrin suitable for use in the compositions, formulations, andmethods herein disclosed preferably are chemically modifiedcyclodextrins. The chemically modified cyclodextrins may includederivatives of α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. Thechemically modified cyclodextrins may include, but are not limited tomethyl-β-cyclodextrin, 2-6-di-O-methyl-β-cyclodextrin, randomlymethylated-β-cyclodextrin, ethyl-β-cyclodextrin,carboxymethyl-P-cyclodextrin, diethylaminoethyl-β-cyclodextrin,2-hydroxypropyl-P-cyclodextrin, 3-hydroxypropyl-β-cyclodextrin,2,3-dihydroxypropyl-β-cyclodextrin, and sulfobutyl ether-β-cyclodextrin.Preferably, the chemically modified cyclodextrin is2-hydroxypropyl-β-cyclodextrin, 3-hydroxypropyl-β-cyclodextrin,2,3-dihydroxypropyl-β-cyclodextrin, and sulfobutyl ether-β-cyclodextrin.More preferably, the chemically modified cyclodextrin is2-hydroxypropyl-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin.Preferably, the degree of substitution for2-hydroxypropyl-β-cyclodextrin is between 3.9 and 5.1.

Preparation of Pharmaceutical Formulations

According to a first aspect of the invention, there is provided a methodof preparing a pharmaceutical formulation for administration as aninjection comprising an inclusion complex of meclizine and a chemicallymodified cyclodextrin with a stoichiometry of 1:>1 mol/mol. Preferably,the cyclodextrin degree of substitution is 0.5-10.0.

According to a second aspect of the invention, there is provided amethod of preparing a pharmaceutical formulation for administration asan injection comprising a solid inclusion complex of meclizine and achemically modified cyclodextrin with a stoichiometry of 1:>1 mol/mol.Preferably, the cyclodextrin degree of substitution is 0.5-10.0.

For example, an inclusion complex is formed between meclizine HCl and achemically modified cyclodextrin, such as 2-hydroxypropyl-β-cyclodextrin(HPBCD), sulfobutyl ether-β-cyclodextrin (SEBCD), or randomlymethylated-β-cyclodextrin (RAMEB) and wherein the molar stoichiometry ofmeclizine to chemically modified cyclodextrin is 1:>1.

According to a third aspect of the invention, there is provided a methodof preparing a pharmaceutical formulation for hypodermic administrationcomprising an inclusion complex of meclizine and a chemically modifiedcyclodextrin with a stoichiometry of 1:>1 mol/mol, which may optionallyinclude a pharmaceutically acceptable anti-oxidant such asacetylcysteine, EDTA, sodium metabisulphite, monothioglycerol, orpotassium nitrate; a pharmaceutically acceptable preservative such asbenzalkonium chloride, bronopol, chlorhexidine gluconate, chlorobutanol,or benzyl alcohol; a pharmaceutically acceptable osmolality adjustingagent, such as glycerol, dextrose, mannitol, or sorbitol; or mixturesthereof.

The preparation of pharmaceutical formulations as herein disclosedinvolves dissolving the chemically modified cyclodextrin in a suitablevolume of aqueous carrier medium (for example, water for injection),removal of oxygen (for example, with nitrogen, inert gas, or freeze-thawunder vacuum), followed by the gradual addition of meclizine to thecyclodextrin solution under vigorous stirring until essentially all ofthe meclizine has been complexed and is in solution. The temperature ofthe cyclodextrin solution may be between 0-80° C. Preferably thetemperature of the cyclodextrin solution is maintained between about20-60° C.

After addition of the meclizine, the solution may be brought to a finalvolume with de-oxygenated aqueous carrier medium. The solution may thenbe sterilized, for example, by filtration and/or aseptically transferredto vials or ampoules. The solution may be transferred directly toampoules for sterilization by autoclaving or irradiation. The vials orampoules may be sealed under an inert gas, such as nitrogen. The molarratio of meclizine to chemically modified cyclodextrin is 1:>1 mol/mol.Preferably, the molar ratio of meclizine to chemically modifiedcyclodextrin is about 1:2 to about 1:30. More preferably, the molarratio of meclizine to chemically modified cyclodextrin is about 1:13mol/mol.

Pharmaceutical Formulations

The composition containing an inclusion complex of meclizine and achemically modified cyclodextrin with a stoichiometry of 1:>1 mol/moland may be formulated as pharmaceutical formulation suitable forinjection. The pharmaceutical formulation may contain a concentration ofmeclizine of 0.05 to 100 mg/ml, preferably 0.25 to 50 mg/ml, morepreferably 0.1 to 10 mg/ml, or even more preferably about 5 mg/ml. Thecomposition may be diluted further with suitable diluents, such as waterfor injection (WFI), aqueous dextrose solution, or aqueous sodiumchloride solution.

The pharmaceutical formulation may have a final pH of 1.0 to 10.0,preferably a pH of 2 to 7, or more preferably a pH of 3.0-5.0. The pHmay be adjusted by methods commonly used in the art, for example, withHCl to reduce the pH or with NaOH to increase the pH. Other acids orbases may be used.

The pharmaceutical formulation may optionally contain a pharmaceuticallyacceptable antioxidant such as acetylcysteine, edetate disodium (EDTA),sodium metabisulphite, monothioglycerol, potassium nitrate, or mixturesthereof, and a pharmaceutically acceptable preservative such asbenzalkonium chloride, bronopol, chlorhexidine gluconate, chlorobutanol,benzyl alcohol, or mixtures thereof, and a pharmaceutically acceptableosmolality adjusting agent such as glycerol, dextrose, mannitol,sorbitol, or mixtures thereof.

The pharmaceutical formulation may be formulated as a solution forinjection, a freeze-dried powder suitable for reconstitution forinjection, a suspension for injection, or an emulsion for injection. Forexample, the pharmaceutical formulations may be freeze-dried orlyophilized to form a solid inclusion complex of meclizine and achemically modified cyclodextrin suitable for reconstitution andinjection. The freeze-dried or lyophilized solid inclusion complex forinjection may be reconstituted prior to administration with a suitablevolume of water for injection, aqueous dextrose, aqueous sodiumchloride, or any other suitable diluent. The reconstituted freeze-driedor lyophilized solid inclusion complex for injection preferably providesa clear, particle free solution suitable for any hypodermicadministration such as, for example, intramuscularly, intravenously,subcutaneously, or intradermally.

During the preparation of the solid inclusion complex, themeclizine-chemically modified cyclodextrin solution may be sterilized byfiltration, whereafter it may be freeze-dried in a sterile environmentand sealed under an inert gas such as nitrogen.

The pharmaceutical formulation may be delivered by syringe, microneedle,or needleless device. The pharmaceutical formulation may be formulatedin conventional ampoules, vials, univials (vials containing two separatecompartments in a single vial), or pre-filled syringes or other devices.

Without being held to any theory, it is believed that the excesschemically modified cyclodextrin present in the pharmaceuticalformulation acts to stabilize the meclizine inclusion complex.

Methods of Treating or Preventing Nausea, Vomiting, or Vertigo

The pharmaceutical formulations as described above may be used in thetreatment and prevention of nausea, vomiting and vertigo conditions, forexample, conditions associated with Meniere's syndrome, nausea andvertigo following anesthesia or in the treatment and prevention ofmotion sickness.

A subject in need thereof of treatment or prevention of nausea,vomiting, or vertigo, is administered a therapeutically effective amountof an injectable formulation consisting essentially of a meclizineinclusion complex with a chemically modified cyclodextrin in an aqueouscarrier medium. Administration of the formulation may be from 0 up to 24hours, from 0 up to 12 hours, from 0 up to 6 hours, or from 0 up to 4hours before the expected nausea or vomiting episode for thepreventative treatment of postoperative nausea and vomiting. Theexpected nausea or vomiting episode may result from chemotherapyadministration or 0-24 hours prior to patient recovery, followinganesthesia. The formulation may optionally include a pharmaceuticallyacceptable anti-oxidant, a pharmaceutically acceptable preservative, apharmaceutically acceptable osmolality adjusting agent, or mixturesthereof. The meclizine concentration is between 0.05 to 100 mg/ml,preferably 0.25 to 50 mg/ml, more preferably 0.1 to 10 mg/ml, or evenmore preferably about 5 mg/ml. The chemically modified cyclodextrin ispreferably HPBCD and the HPBCD preferably has a degree of substitutionof between about 3.9 to about 5.1. The aqueous carrier medium preferablyhas a pH of between about 2 and about 7. The molar ratio of meclizine toHPBCD is preferably 1:>1.

The following examples are illustrative and not to be interpreted aslimiting or restrictive. Notwithstanding that the numerical ranges andparameters setting forth the broad scope of the invention areapproximations, the numerical values set forth in the specific examplesare reported as precisely as possible. Any numerical value, however,inherently contain certain errors necessarily resulting from thestandard deviation found in their respective measurements. For example,the use of the term “about” in reference to a numerical value refers toa range of approximately ±10 percent unless specified otherwise. In thefollowing examples, meclizine dihydrochloride monohydrate was used.

EXAMPLE 1

Citric acid (0.1M) buffer solutions are prepared with pH's of 1.0; 2.0;3.0; 4.0, and 5.0 in ddH₂O (de-oxygenated water by purging with nitrogengas). 2 ml of each buffer are placed in 4 ml vials and 2 ml ddH₂O isplaced in a 4 ml vial. 20 mg meclizine HCl is added to each vial. Thevials are sealed and are shaken on an orbital shaker for 24 hours at 200rpm. Following the shaking, the vial contents are filtered through 0.45μm filters to remove any excess solute. The remaining solution isassayed by HPLC for meclizine content. As shown in FIG. 1, the aqueoussolubility of meclizine decreases with an increase in pH from about 1.5mg/ml at pH 1.0 to below the limit of detection at about pH 5.0. Theaqueous solubility of meclizine in ddH₂O is found to be about 3.8 mg/mland has a measured pH of about 2.0.

EXAMPLE 2

FIG. 1A depicts solubility data of meclizine complexed withnon-chemically modified cyclodextrins (α-CD at 0-100 mg/ml, γ-CD at 200mg/ml), chemically modified cyclodextrins (HPBCD and SBECD) at 200mg/ml, and with no CD complexation in ddH₂O. Solutions were prepared byadding excess meclizine to ddH₂O samples with varying quantities of thedifferent cyclodextrins. These samples were shaken for 24 hours at 200rpm. Following the shaking, the vial contents were filtered through 0.45μm filters to remove any excess solute. The remaining solution wasassayed by HPLC for meclizine content. The data of FIG. 1A showsimproved solubility of meclizine with all of the cyclodextrin used anddemonstrates that the aqueous solubility of meclizine is enhanced in thepresence of cyclodextrins.

EXAMPLE 3

Five HPBCD and five SBECD solutions in 0.5 M citric acid buffer (pH of3.0) are prepared, with HPBCD and SBECD concentrations of 50; 100; 150and 200 mg/ml. 3 ml of the various buffered HPBCD and SBECD solutionsare placed in 4 ml vials. 75-100 mg meclizine is added to each vial,such that excess meclizine is provided. The vials are sealed and areshaken on an orbital shaker for 24 hours at 200 rpm and 25° C. Followingthe shaking, the vials are filtered through 0.45 μm filters to removeany excess solute. The remaining solution is assayed by HPLC formeclizine content. As shown in FIG. 2, the aqueous solubility ofmeclizine at pH 3.0 increases from about 0.30 mg/ml (with no HPBCD orSBECD) in a linear fashion to about 20 mg/ml at an HPBCD concentrationof 200 mg/ml and 7.10 mg/ml at a SBECD concentration of 200 mg/ml. Thus,the meclizine aqueous solubility is enhanced with an increase inchemically modified cyclodextrin concentration.

FIG. 2A depicts the solubility of meclizine in non-chemically modifiedcyclodextrins (α-CD at 0-100 mg/ml, γ-CD at 200 mg/ml) with HPBCD andSBECD at 200 mg/ml compared with no CD in 0.5 M citric buffer. The datashows improved solubility of meclizine in HPBCD at higher pH, especiallyabove pH of about 5 compared with the non-chemically modified CD's.While the non-chemically modified ACD enhances the solubility ofmeclizine to a similar extent as that seen for HPBCD and at a lowercyclodextrin concentration (100 mg/ml ACD), toxicological concerns ofthese quantities of ACD may not be viable for a parenteral formulation.

EXAMPLE 4

Five HPBCD and five SBECD solutions in 0.5 M citric acid buffer (pH of4.0) are prepared, with HPBCD and SBECD concentrations of 0; 50; 100;150 and 200 mg/ml. 3 ml of the various buffered HPBCD and SBECDsolutions are placed in 4 ml vials. 50-100 mg meclizine is added to eachvial, such that excess meclizine is available. The vials are sealed andare shaken on an orbital shaker for 24 hours at 200 rpm and 25° C.Following the shaking, the vials are filtered through 0.45 μm filters toremove any excess solute. The remaining solution is assayed by HPLC formeclizine content. As shown in FIG. 3, the aqueous solubility ofmeclizine at pH 4.0 increases from about 0.01 mg/ml (with no HPBCD orSBECD) in a linear fashion to about 21 mg/ml at an HPBCD concentrationof 200 mg/ml and 10 mg/ml at an SBECD concentration of 200 mg/ml. Thus,the meclizine aqueous solubility is enhanced with an increase inchemically modified cyclodextrin concentration at higher pH.

EXAMPLE 5

2000 mg HPBCD is weighed off and dissolved in 25 ml ddH₂O at ambienttemperature. The volume is brought to 35 ml with ddH₂O. 200 mg meclizineis added to the HPBCD solution and is vigorously stirred for 60 minutes,during which time essentially all of the meclizine is complexed and goesinto solution. The pH is measured to be 2.1 and is adjusted to 3.5 witha 0.5 M NaOH solution. The meclizine-HPBCD solution is made to 40 mlvolume with de-oxygenated ddH₂O. The meclizine-HPBCD solution is sterilefiltered through 0.22 μm filters and filled aseptically into 1 ml vials.The meclizine content and stability was determined and monitored by HPLCon a monthly basis. HPLC analysis demonstrated that the meclizine-HPBCDsolution was stable at 25° C. and at 40° C. for at least 6 months.

EXAMPLE 6

2000 mg HPBCD is weighed off and dissolved in 25 ml ddH₂O at ambienttemperature. The volume is brought to 35 ml with ddH₂O. 200 mgmonothioglycerol is added to the solution. 200 mg meclizine is added tothe HPBCD and monothioglycerol solution and is vigorously stirred,during which time essentially all of the meclizine is complexed and goesinto solution. The pH is measured to be 2.1 and is adjusted to 3.5 witha 0.5 M NaOH solution. The meclizine-HPBCD solution is made to 40 mlvolume with ddH₂O. The meclizine-HPBCD solution is sterile filteredthrough 0.22 μm filters and filled aseptically into 1 ml vials. Themeclizine content and stability was determined and monitored by HPLC ona monthly basis. HPLC analysis demonstrated that the meclizine-HPBCDsolution was stable at 25° C. and at 40° C. for at least 3 months.

EXAMPLE 7

2000 mg HPBCD is weighed off and dissolved in 25 ml ddH₂O at ambienttemperature. The volume is brought to 35 ml with de-oxygenated WFI. 20mg edetate disodium is added to the solution. 200 mg meclizine is addedto the HPBCD and edetate disodium solution and is vigorously stirred,during which time essentially all of the meclizine is complexed and goesinto solution. The pH is measured to be 2.2 and is adjusted to 3.5 witha 0.5 M NaOH solution. The meclizine-HPBCD solution is made to 40 mlvolume with de-oxygenated WFI. The meclizine-HPBCD solution is sterilefiltered through 0.22 μm filters and filled aseptically into 1 ml vials.The meclizine content and stability was determined and monitored by HPLCon a monthly basis. HPLC analysis demonstrated that the meclizine-HPBCDsolution was stable at 25° C. and at 40° C. for at least 6 months.

EXAMPLE 8

2000 mg HPBCD is weighed off and dissolved in 25 ml ddH₂O at ambienttemperature. The volume is brought to 35 ml with ddH₂O. 200 mg meclizineis added to the HPBCD solution and is vigorously stirred for 60 minutes.The pH is adjusted to pH 3.5 with a 0.5 M NaOH solution. Themeclizine-HPBCD solution is made to 40 ml volume with ddH₂O. Themeclizine-HPBCD solution is sterile filtered through 0.22 μm filters andfilled aseptically into 1 ml vials. The vials are freeze-dried toproduce a solid meclizine-HPBCD inclusion complex and sealed. The solidmeclizine-HPBCD inclusion complex is readily dissolved duringreconstitution prior to use. The meclizine content and stability wasdetermined and monitored by HPLC on a monthly basis. The solidmeclizine-HPBCD inclusion complex was found to be stable at 25° C. andat 40° C. for at least 6 months.

EXAMPLE 9

8000 mg SBECD is weighed off and dissolved in 30 ml ddH₂O at ambienttemperature. The volume is brought to 35 ml with ddH₂O. 200 mg meclizineis added to the SBECD solution and is vigorously stirred, during whichtime essentially all of the meclizine is complexed and goes intosolution. The pH is adjusted to 4.0 with a 0.5 M NaOH solution. Themeclizine-SBECD solution is made to 40 ml volume with ddH₂O. Themeclizine-SBECD solution is sterile filtered through 0.22 μm filters andfilled aseptically into 2 ml injection vials and stoppered. Themeclizine content was determined by HPLC.

EXAMPLE 10

A 300 mg/ml HPBCD solution is prepared by dissolving 1500 mg HPBCD in 40ml 0.5 M acetate buffer (sparged with nitrogen gas) at ambienttemperature, after which it is made to 50 ml volume with the 0.5 Macetate buffer. 100 mg meclizine is added to 20 ml of the 300 mg/mlHPBCD solution and is vigorously stirred, during which time essentiallyall of the meclizine is complexed and goes into solution. The pH ismeasured to be 4.0 and the meclizine-HPBCD solution is sterile filteredthrough 0.22 μm filters and filled aseptically into 2 ml injection vialsand stoppered. The meclizine content and stability was determined andmonitored by HPLC on a monthly basis. HPLC analysis demonstrated thatthe 5 mg/ml meclizine-HPBCD solution was stable at 25° C. and at 40° C.for at least 3 months and the pH remained at 4.

EXAMPLE 11

A 300 mg/ml HPBCD solution is prepared by dissolving 1500 mg HPBCD in 40ml 0.5 M acetate buffer (sparged with nitrogen gas) at ambienttemperature, after which it is made to 50 ml volume with the 0.5 Macetate buffer. 500 mg meclizine is added to 20 ml of the 300 mg/mlHPBCD solution and is vigorously stirred, during which time essentiallyall of the meclizine is complexed and goes into solution. The pH ismeasured to be 4.0 and the meclizine-HPBCD solution is sterile filteredthrough 0.22 μm filters and filled aseptically into 2 ml injection vialsand stoppered. The meclizine content and stability was determined andmonitored by HPLC on a monthly basis. HPLC analysis demonstrated thatthe 25 mg/ml meclizine-HPBCD solution was stable at 25° C. and at 40° C.for at least 3 months and the pH remained at 4.

Thus, we have demonstrated that meclizine forms inclusion complexes withcyclodextrins in solution and that it is possible to produce a stable,substantially clear formulations, the formulations being provided withan aqueous carrier pH of about 2 to about 7, the viable formulations ofmeclizine being suitable for injection.

1. A method of treating a vertigo condition in a subject in needthereof, the method comprising: injecting the subject with apharmaceutically acceptable formulation consisting essentially of: atherapeutically effective amount of meclizine; a chemically modifiedcyclodextrin, wherein the molar ratio of the meclizine to the chemicallymodified cyclodextrin is 1:>1; an aqueous carrier medium having a pHbetween about 2 to about 7; and optionally a pharmaceutically acceptablepreservative, a pharmaceutically acceptable antioxidant, apharmaceutically acceptable osmolality adjusting agent, or mixturesthereof.
 2. The method of claim 1, wherein the vertigo condition isbenign paroxysmal positional vertigo.
 3. The method of claim 1, whereinthe molar ratio of meclizine to the chemically modified cyclodextrin isbetween about 1:2 to about 1:30.
 4. The method of claim 1, wherein themolar ratio of meclizine to the chemically modified cyclodextrin isabout 1:13.
 5. The method of claim 1, wherein the chemically modifiedcyclodextrin is 2-hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, or mixtures thereof.
 6. The method of claim 1,wherein the chemically modified cyclodextrin has a degree ofsubstitution between 0.5 to 10.0.
 7. The method of claim 1, wherein thepH of the aqueous carrier medium is between about 3 to about
 5. 8. Aninjectable pharmaceutical formulation for treating a vertigo conditionof a subject, the injectable pharmaceutical formulation consistingessentially of: a therapeutically effective amount of meclizine; a molarexcess of cyclodextrin selected from the group consisting of2-hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin; anaqueous carrier medium, the aqueous carrier medium having a pH betweenabout 2 to about 7; and optionally a pharmaceutically acceptablepreservative, a pharmaceutically acceptable antioxidant, apharmaceutically acceptable osmolality adjusting agent, or combinationthereof.
 9. The injectable pharmaceutical formulation of claim 8,wherein the molar ratio of meclizine to the chemically modifiedcyclodextrins is between about 1:2 to about 1:30.
 10. The injectablepharmaceutical formulation of claim 8, wherein the molar ratio of themeclizine to the chemically modified cyclodextrins is about 1:13. 11.The injectable pharmaceutical formulation of claim 8, wherein the2-hydroxypropyl-β-cyclodextrin has a degree of substitution betweenabout 3.9 to about 5.1.
 12. The injectable pharmaceutical formulation ofclaim 8, wherein the pH of the aqueous carrier medium is between about 3to about
 5. 13. An injectable pharmaceutical formulation for treatingand/or preventing a vertigo, nausea, or vomiting condition in a subjectin need thereof, the injectable pharmaceutical formulation prepared bythe steps: providing a chemically modified cyclodextrin solution in apharmaceutically acceptable aqueous carrier medium; combining atherapeutically effective amount of meclizine with the chemicallymodified cyclodextrin solution; wherein the molar ratio of the meclizineto the chemically modified cyclodextrin solution is 1:>1; adjusting thepharmaceutically acceptable aqueous carrier medium pH to between about 2to about 7; and optionally adding a pharmaceutically acceptablepreservative, a pharmaceutically acceptable antioxidant, apharmaceutically acceptable osmolality adjusting agent, or combinationthereof.
 14. A method of treating or preventing a nausea or vomitingcondition in a subject in need thereof, the method comprising: injectinga subject with a pharmaceutically acceptable formulation consistingessentially of: a therapeutically effective amount of meclizine; achemically modified cyclodextrin, wherein the molar ratio of themeclizine to the chemically modified cyclodextrin is 1:>1; an aqueouscarrier medium having a pH between about 2 to about 7; and optionally apharmaceutically acceptable preservative, a pharmaceutically acceptableantioxidant, a pharmaceutically acceptable osmolality adjusting agent,or mixtures thereof.
 15. The method of claim 14, wherein the subject isadministered the therapeutically effective amount of meclizine pre-,peri-, or post-operatively.
 16. The method of claim 14, wherein thesubject is administered the therapeutically effective amount ofmeclizine pre-, peri-, or post-chemotherapy treatment.
 17. The method ofclaim 14, wherein the molar ratio of meclizine to the chemicallymodified cyclodextrin is between about 1:2 to about 1:30.
 18. The methodof claim 14, wherein the molar ratio of meclizine to the chemicallymodified cyclodextrin is about 1:13.
 19. The method of claim 14, whereinthe chemically modified cyclodextrin is 2-hydroxypropyl-β-cyclodextrin,sulfobutyl ether-β-cyclodextrin, or mixtures thereof.
 20. The method ofclaim 14, wherein the chemically modified cyclodextrin has a degree ofsubstitution between about 0.5 to about 10.0.
 21. The method of claim14, wherein the pH of the aqueous carrier medium is between about 3 toabout
 5. 22. An injectable pharmaceutical formulation for treating orpreventing a nausea or vomiting condition, the injectable pharmaceuticalformulation consisting essentially of: a therapeutically effectiveamount of meclizine; a molar excess of cyclodextrin selected from thegroup consisting of 2-hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin; an aqueous carrier medium, the aqueous carriermedium having a pH between about 3 to about 7; and optionally apharmaceutically acceptable preservative, a pharmaceutically acceptableantioxidant, a pharmaceutically acceptable osmolality adjusting agent,or combination thereof.
 23. The injectable pharmaceutical formulation ofclaim 22, wherein the molar ratio of meclizine to the chemicallymodified cyclodextrins is between about 1:2 to about 1:30.
 24. Theinjectable pharmaceutical formulation of claim 22, wherein the molarratio of the meclizine to the chemically modified cyclodextrins is about1:13.
 25. The injectable pharmaceutical formulation of claim 22, whereinthe 2-hydroxypropyl-β-cyclodextrin has a degree of substitution betweenabout 3.9 to about 5.1.